-- UB researchers have discovered how mutations in parkin
disrupt proper function of dopamine, the neurotransmitter that
controls body movement.

-- They found that parkin mutations disrupt the precise actions
of dopamine and produce more free radicals, which in turn destroy
the dopamine neurons, leading to Parkinson's disease.

-- This is the first study to use live human neurons to
investigate what role parkin plays in Parkinson's disease; this
dramatic advance was made possible by the use of induced
pluripotent stem cells.

-- Funding was provided by the Michael J. Fox Foundation for
Parkinson's Research; the National Institutes of Health; SUNY
REACH, a research network of SUNY academic medical centers; and
NYSTEM, New York State's stem cell initiative.

BUFFALO, N.Y. -- Parkinson's disease researchers at the
University at Buffalo have discovered how mutations in the parkin
gene cause the disease, which afflicts at least 500,000 Americans
and for which there is no cure.

The results are published in the current issue of Nature
Communications.

The UB findings reveal potential new drug targets for the
disease as well as a screening platform for discovering new
treatments that might mimic the protective functions of parkin. UB
has applied for patent protection on the screening platform.

"This is the first time that human dopamine neurons have ever
been generated from Parkinson's disease patients with parkin
mutations," says Jian Feng, PhD, professor of physiology and
biophysics in the UB School of Medicine and Biomedical Sciences and
the study's lead author.

As the first study of human neurons affected by parkin, the UB
research overcomes a major roadblock in research on Parkinson's
disease and on neurological diseases in general.

The problem has been that human neurons live in a complex
network in the brain and thus are off-limits to invasive studies,
Feng explains.

"Before this, we didn't even think about being able to study the
disease in human neurons," he says. "The brain is so fully
integrated. It's impossible to obtain live human neurons to
study."

But studying human neurons is critical in Parkinson's disease,
Feng explains, because animal models that lack the parkin gene do
not develop the disease; thus, human neurons are thought to have
"unique vulnerabilities."

"Our large brains may use more dopamine to support the neural
computation needed for bipedal movement, compared to quadrupedal
movement of almost all other animals," he says.

Since in 2007, when Japanese researchers announced they had
converted human cells to induced pluripotent stem cells (iPSCs)
that could then be converted to nearly any cells in the body,
mimicking embryonic stem cells, Feng and his UB colleagues saw
their enormous potential. They have been working on it ever
since.

"This new technology was a game-changer for Parkinson's disease
and for other neurological diseases," says Feng. "It finally
allowed us to obtain the material we needed to study this
disease."

The current paper is the fruition of the UB team's ability to
"reverse engineer" human neurons from human skin cells taken from
four subjects: two with a rare type of Parkinson's disease in which
the parkin mutation is the cause of their disease and two healthy
subjects who served as controls.

"Once parkin is mutated, it can no longer precisely control the
action of dopamine, which supports the neural computation required
for our movement," says Feng.

The UB team also found that parkin mutations prevent it from
tightly controlling the production of monoamine oxidase (MAO),
which catalyzes dopamine oxidation.

"Normally, parkin makes sure that MAO, which can be toxic, is
expressed at a very low level so that dopamine oxidation is under
control," Feng explains. "But we found that when parkin is mutated,
that regulation is gone, so MAO is expressed at a much higher
level. The nerve cells from our Parkinson's patients had much
higher levels of MAO expression than those from our controls. We
suggest in our study that it might be possible to design a new
class of drugs that would dial down the expression level of
MAO."

He notes that one of the drugs currently used to treat
Parkinson's disease inhibits the enzymatic activity of MAO and has
been shown in clinical trials to slow down the progression of the
disease.

Parkinson's disease is caused by the death of dopamine neurons.
In the vast majority of cases, the reason for this is unknown, Feng
explains. But in 10 percent of Parkinson's cases, the disease is
caused by mutations of genes, such as parkin: the subjects with
Parkinson's in the UB study had this rare form of the disease.

"We found that a key reason for the death of dopamine neurons is
oxidative stress due to the overproduction of MAO," explains Feng.
"But before the death of the neurons, the precise action of
dopamine in supporting neural computation is disrupted by parkin
mutations. This paper provides the first clues about what the
parkin gene is doing in healthy controls and what it fails to
achieve in Parkinson's patients."

He noted in this study that these defects are reversed by
delivering the normal parkin gene into the patients' neurons, thus
offering hope that these neurons may be used as a screening
platform for discovering new drug candidates that could mimic the
protective functions of parkin and potentially even lead to a cure
for Parkinson's.

While the parkin mutations are only responsible for a small
percentage of Parkinson's cases, Feng notes that understanding how
parkin works is relevant to all Parkinson's patients. His ongoing
research on sporadic Parkinson's disease, in which the cause is
unknown, also points to the same direction.

The University at Buffalo is a premier research-intensive public
university, the largest and most comprehensive campus in the State
University of New York. UB's more than 28,000 students pursue their
academic interests through more than 300 undergraduate, graduate
and professional degree programs. Founded in 1846, the University
at Buffalo is a member of the Association of American
Universities.